Protective effect of the T112 PrP variant in sheep challenged with bovine spongiform encephalopathy

Saunders, Ginny C.; Lantier, Isabelle; Cawthraw, Saira; Berthon, Patricia; Moore, Jerry D.; Arnold, Mark; Windl, Otto; Simmons, Marion; Andréoletti, Olivier; Bellworthy, S. J.; Lantier, Frédéric

doi:10.1099/vir.0.012724-0

Cited by 28 publications

(29 citation statements)

References 54 publications

(47 reference statements)

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“…The BSE incubation period did not alter with the doses used, but there was an association of codon 141 with the length of the incubation period in that animals of the ARQ/ARQ genotype had the shortest incubation periods if they were also LL 141 , longer if FF 141 , and longer still if LF 141 . New Zealand Cheviot sheep have a polymorphism at codon 168 that has been associated with BSE resistance (22), and codon 112 has been shown in other sheep also to be associated with differences in BSE (47). However, in the sheep in the present study, codons 168 and 112 did not vary, except in one single animal that was PL 168 , and no additional codon variants were found.…”

Section: Discussioncontrasting

confidence: 51%

“…In our previous studies we used a dose of 5 g of cattle BSE brain per (adult) sheep and this resulted in clinical disease at an average incubation period of around 800 days (16). The 5-g dose, or even larger amounts, has become the normal oral dose when clinical disease is required for pathogenesis studies in our own and other labs (3,47,52,59). In the present study, the lower doses (ranging from 0.1 g to 1 g per animal) were chosen such that the sheep in the adult group would not all become clinically affected by BSE.…”

Section: Discussionmentioning

confidence: 99%

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Susceptibility of Young Sheep to Oral Infection with Bovine Spongiform Encephalopathy Decreases Significantly after Weaning

Hunter

Houston

Foster

et al. 2012

J Virol

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bBovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) (or prion disease) that is readily transmissible to sheep by experimental infection and has the shortest incubation period in animals with the ARQ/ARQ PRNP genotype (at codons 136, 154, and 171). Because it is possible that sheep in the United Kingdom could have been infected with BSE by being fed contaminated meat and bone meal supplements at the same time as cattle, there is considerable interest in the responses of sheep to BSE inoculation. Epidemiological evidence suggests that very young individuals are more susceptible to TSE infection; however, this has never been properly tested in sheep. In the present study, low doses of BSE were fed to lambs of a range of ages (ϳ24 h, 2 to 3 weeks, 3 months, and 6 months) and adult sheep. The incidence of clinical BSE disease after inoculation was high in unweaned lambs (ϳ24 h and 2 to 3 weeks old) but much lower in older weaned animals The incubation period was also found to be influenced by the genotype at codon 141 of the PRNP gene, as lambs that were LF heterozygotes had a longer mean incubation period than those that were homozygotes of either type. The results suggest that sheep in the United Kingdom would have been at high risk of BSE infection only if neonatal animals had inadvertently ingested contaminated supplementary foodstuffs.T ransmissible spongiform encephalopathies (TSEs) are prion diseases that affect many mammals and are associated with the presence of the protein PrP Sc , a protease-resistant form of a normal host protein, PrP C . PrP Sc is believed to form all or part of the infectious agent (44). The natural sheep TSE is scrapie; however, sheep can also be experimentally infected with bovine spongiform encephalopathy (BSE) by several routes, including intracerebral, oral (17), and intravenous (28). The manifestation of clinical signs of BSE following inoculation depends upon a number of factors, the most important being the PRNP genotype. In the Neuropathogenesis Unit, Edinburgh, United Kingdom (NPU), Cheviot sheep, animals homozygous for the ARQ PRNP gene allele (codons 136, 154, and 171 indicated in order) are most susceptible (23). However, for reasons that are currently unknown, a various number of adult ARQ/ARQ sheep will survive a challenge with BSE (16). Understanding this aspect of resistance is of fundamental importance. One potential influence on disease outcome following infection with any TSE is the age at which the individual is challenged. Because of the etiology of scrapie, which suggests that in sheep the risk for infection is very high during the perinatal period, many sheep challenge studies, including the study described in reference 3, have used young lambs rather than adult sheep as infection models. In addition, epidemiological studies in cattle (15) have suggested that in general, younger individuals are more susceptible to infection with BSE, and studies in human beings have shown that more individuals at relatively young ages have b...

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Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Susceptibility of Young Sheep to Oral Infection with Bovine Spongiform Encephalopathy Decreases Significantly after Weaning

Hunter

Houston

Foster

et al. 2012

J Virol

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“…In ARQ/ARQ sheep other additional dimorphisms, which are thought to reduce the risk of having scrapie and/or BSE, namely M112T (Laegreid et al, 2008;Saunders et al, 2009), P168L (Goldmann et al, 2006), M137T (Vaccari et al,. 2009;Maestrale et al, 2009) and I142K (Vaccari et al, 2007), may also give resistance to PrP Sc deposition in the placenta.…”

Section: Several Descriptive Data Suggest That Prpmentioning

confidence: 99%

“…It was recently demonstrated that amino acid substitutions at some of these polymorphisms are associated with resistance to scrapie and bovine spongiform encephalopathy (BSE) in ARQ/ARQ sheep (Vaccari et al, 2007(Vaccari et al, , 2009Laegreid et al, 2008;Maestrale et al, 2009;Saunders et al, 2009). Consequently, it is of interest whether they are also related to PrP Sc deposition in the placenta of scrapie-infected ewes.…”

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confidence: 99%

Association of N176K and L141F dimorphisms of the PRNP gene with lack of pathological prion protein deposition in placentas of naturally and experimentally scrapie-affected ARQ/ARQ sheep

Santucciu

Maestrale

Madau

et al. 2010

Journal of General Virology

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“…Other variants also influence susceptibility, for example, H 154 (where H is histidine) (13,(24)(25)(26)(27)(28)(29)(30). Together, this evidence has led to policies for eradication of scrapie in sheep breeds by focusing on codons 136, 154, and 171, in which the different alleles are designated, in respective order, ARQ (the wild type), VRQ, AHQ, and ARR (31,32).…”

mentioning

confidence: 99%

Prion Type-Dependent Deposition of PRNP Allelic Products in Heterozygous Sheep

Langeveld

Jacobs

Hunter

et al. 2016

J Virol

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Susceptibility or resistance to prion infection in humans and animals depends on single prion protein (PrP) amino acid substitutions in the host, but the agent's modulating role has not been well investigated. Compared to disease incubation times in wild-type homozygous ARQ/ARQ (where each triplet represents the amino acids at codons 136, 154, and 171, respectively) sheep, scrapie susceptibility is reduced to near resistance in ARR/ARR animals while it is strongly enhanced in VRQ/VRQ carriers. Heterozygous ARR/VRQ animals exhibit delayed incubation periods. In bovine spongiform encephalopathy (BSE) infection, the polymorphism effect is quite different although the ARR allotype remains the least susceptible. In this study, T ransmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal neurological diseases occurring in some mammalian species, including humans. The TSE agent or prion is characterized by the pivotal role of the host prion protein (PrP) that in disease appears aggregated and structurally abnormal and is named PrP Sc , where "Sc" refers to scrapie in small ruminants, which was recognized in the 18th century in Spanish Merino sheep (1). In healthy situations PrP is a cellular membrane protein (PrP C ) and fully susceptible to proteases, while its PrP Sc isoform is partially resistant to digestion with proteinase K (PK), usually leading to an N-terminally shortened protein called PrP res that still retains the associated infectivity (2-4).From many studies it is obvious that TSEs occur in distinct phenotypic forms that are recognized as TSE or prion disease types, such as classical scrapie in sheep and goat, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy (BSE) in cattle (5-15). In the experimental situation, these types can be considered strains when they are subpassaged to homogeneity in rodent bioassays (16)(17)(18)(19)(20). Susceptibility (and resistance) to animal and human prion diseases, either under infectious or spontaneous conditions, is dependent on single amino acid substitutions in the host's PrP sequence. In most species such substitutions are naturally occurring polymorphisms (7,10,(21)(22)(23)(24).In sheep two PrP polymorphisms in the PrP sequence, V 136 and R 171 (where V is valine and R is arginine, according to the singleletter code used by the IUPAC-IUB Joint Commission on Biochemical Nomenclature), provide, respectively, high and very low susceptibilities to natural scrapie compared to the homozygous

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Protective effect of the T112 PrP variant in sheep challenged with bovine spongiform encephalopathy

Cited by 28 publications

References 54 publications

Susceptibility of Young Sheep to Oral Infection with Bovine Spongiform Encephalopathy Decreases Significantly after Weaning

Susceptibility of Young Sheep to Oral Infection with Bovine Spongiform Encephalopathy Decreases Significantly after Weaning

Association of N176K and L141F dimorphisms of the PRNP gene with lack of pathological prion protein deposition in placentas of naturally and experimentally scrapie-affected ARQ/ARQ sheep

Prion Type-Dependent Deposition of PRNP Allelic Products in Heterozygous Sheep

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